There are a number of reports in the literature demonstrating similarities and differences in the actions of exogenous and endogenous cannabinoids. The similarities in their effects suggest that exogenous cannabinoids produce their effects through the endogenous system. Evidence suggests that anandamide differs from THC, in that its affinity for CB1 receptors can only be seen in the presence of a FAAH inhibitor. This difference supports the hypothesis that anandamide causes some of its effects by mechanisms other than those involved in THC activity. The ubiquitous nature of endocannabinoids has led to the hypothesis that they are involved in a plethora of physiological functions. However, the nature of the involvement of anandamide in any single physiological process has yet to be determined. Due to the diversity of activities between anandamide and THC that have been reported, it is critical to determine the mechanism by which each is producing its effects. In this proposal we have chosen to evaluate the role of anandamide and other endocannabinoids in the behavioral effects of exogenous cannabinoids, as well as to elucidate their own effects in these measures. We will examine the role of selected intracellular processes in the actions of cannabinoids by inhibiting selected steps in a number of signal transduction systems, and determining how the inhibition alters the acute effects of THC, anandamide and its analogs. We will be especially cognizant of similarities and differences between the effects of inhibiting a specific signal transduction step on exogenous verses endogenous cannabinoids, as well as their analogs. Measures to be used in these studies are the four behaviors included in the tetrad used to quantify the effects of the cannabinoids. We will also determine the effect of inhibiting signal transduction pathways on the expression of tolerance to THC, anandamide and its analogs. We have demonstrated that tolerance develops to anandamide, but it is much less robust than that seen with THC. We have shown that cross-tolerance occurs between these two classes of cannabinoids and their analogs. This latter observation suggests that there are similarities in the mechanisms by which tolerance develops to these drugs.